Classifications

C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings

C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members

C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

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C07D—HETEROCYCLIC COMPOUNDS

C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom

C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom

C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members

C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms

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C07D—HETEROCYCLIC COMPOUNDS

C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members

C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members

C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom

C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms

C07D213/36—Radicals substituted by singly-bound nitrogen atoms

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C07D—HETEROCYCLIC COMPOUNDS

C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings

C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members

C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms

C07D233/62—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with triarylmethyl radicals attached to ring nitrogen atoms

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C07D—HETEROCYCLIC COMPOUNDS

C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms

C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings

C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

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C07D—HETEROCYCLIC COMPOUNDS

C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms

C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings

C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2.] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings

C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2.] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain

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C07D—HETEROCYCLIC COMPOUNDS

C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom

C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings

C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

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C07D—HETEROCYCLIC COMPOUNDS

C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom

C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings

C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Abstract

Compositions of non-steroidal glucocorticoid antagonists for treating glaucoma or ocular hypertension and methods for their use are disclosed.

Description

This application is a continuation of U.S. Ser. No. 08/858,298, filed on May 19, 1997, now abandoned, which is a continuation of U.S. Ser. No. 08/631,041, filed Apr. 12, 1996, now abandoned, which is a continuation of U.S. Ser. No. 08/268,086, filed on Jun. 28, 1994, now abandoned.

This invention is directed to the use of non-steroidal glucocorticoid antagonists for treating glaucoma and ocular hypertension.

BACKGROUND OF THE INVENTION

Current glaucoma therapy involves treating an important risk factor for the disease, that is, elevated intraocular pressure (IOP). For example, beta-blockers and carbonic anhydrase inhibitors lower IOP by decreasing aqueous humor production. It would be advantageous to control IOP without decreasing aqueous humor production as the aqueous humor is the fluid that nourishes the anterior parts of the eye that are devoid of blood vessels, such as, the cornea and the lens.

SUMMARY OF THE INVENTION

Non-steroidal glucocorticoid antagonists (NSGAs) and their pharmaceutical formulations are useful for treating glaucoma and ocular hypertension. The invention is also directed to methods for controlling glaucoma and ocular hypertension using NSGAs, some of which are novel.

It is known that trabecular meshwork cells have glucocorticoid receptors and that glucocorticoid binding with these receptors causes a change in trabecular as meshwork cell gene expression. Known manifestations of this change include a reorganization of the cytoskeleton (Wilson, et al., Dexamethasone induced ultrastructural changes in cultured human trabecular meshwork cells, Cur. Eye Res. 12: 783-793 (1993) and Clark, et al., Glucocorticoid-induced formation of cross-linked actions networks in cultured human trabecular meshwork cells, Invest. Ophthalmol. Vis. Sci. 35: 281-294 (1994)) and increased deposition of the extracellular matrix material in trabecular meshwork cells. As a result, the trabecular meshwork becomes “clogged” and unable to perform one of its most critical functions, that is, serving as a gateway for aqueous humor flow from the anterior chamber of the eye. When the aqueous humor flow out of the eye via the trabecular meshwork is diminished, the intraocular pressure of the eye rises. If this state of elevated intraocular pressure is maintained or frequently occurs, the optic nerve head can be damaged resulting in the loss of visual field. Loss of visual field is the hallmark symptom associated with glaucoma.

Endogenous glucocorticoids may be responsible for producing the changes in the trabecular meshwork that lead to ocular hypertension and glaucoma. It is believed that non-steroidal glucocorticoid antagonists bind to the glucocorticoid receptor in trabecular meshwork cells, and thereby prevent binding of endogenous glucocorticoids to the glucocorticoid receptor. They may also displace endogenous glucocorticoids which are bound to glucocorticoid receptors. Use of the compounds of the present invention is advantageous over existing therapies in that the compounds function at the disease site, that is, at the trabecular meshwork cell level, rather than indirectly addressing elevated intraocular pressure by suppressing aqueous humor formation.

Ketoconazole and clotrimazole are known glucocorticoid antagonists. (Loose, et al., Ketoconazole Binds to Glucocorticoid Receptors and Exhibits Glucocorticoid Antagonist Activity in Cultured Cells, J. Clin. Invest. 72: 404-408 (1983)). They are not known to be useful in treating or controlling glaucoma.

Non-steroidal glucocorticoid antagonists which are particularly useful in treating glaucoma or ocular hypertension have the following structure:

a. To a stirred, ice-cooled solution of 2-fluorofluorenone (2.0 g, 10 mmol) in 15 mL of dry THF under N2 was added 10 mL of 2.4 M phenyllithium solution in cyclohexane-Et2O (7:3), keeping T<20° C. The mixture was quenched with water and the product isolated with EtOAc and purified by flash chromatography (7% EtOAc-hexanes) to give 2.52 g (90%) of 2-fluoro-9-phenylfluoren-9-ol.

b. A solution of the above alcohol (0.57 g, 2.1 mmol) and imidazole (0.56 g, 8.4 mmol) in 6 mL of HOAc was heated to reflux under N2 for 9.5 h. The crude product was isolated as described for (2) and purified by flash chromatography (30 g SiO2, 50% EtOAc-hexanes) giving 0.40 g (59%) of a foam. This material was recrystallized from EtOAc to give 0.19 g of (3), m.p. 191.5°-194° C.

A solution of diphenyl-2-pyridylmethanol (0.50 g, 1.9 mmol) and imidazole (0.50 g, 7.4 mmol) in 2 mL of EtCO2H was heated to reflux under N2 for 7 h. The crude product was isolated as described for (2) and purified by flash chromatography (60 g SiO2, EtOAc) to give 0.08 g (13.5%) of a yellow solid. This material was further purified by trituration (4:1 hexanes-Et2O) followed by recrystallization from EtOAc to give 0.03 g of (4), m.p. 214.5°-216.5° C.

To a stirred solution of tris(4-chlorophenyl)methanol (0.36 g, 1.0 mmol) and imidazole (0.20 g, 2.9 mmol) in 2 mL of CH2Cl2 under N2 at RT was added 0.40 mL (2.0 mmol) of trimethylsilyl triflate. After 1 h, the crude product was isolated as described for (2) and purified by flash chromatography (10% EtOAc-hexanes→EtOAc) to give 0.25 g of a semisolid. This material was triturated with 5% Et2O-hexanes to give 0.20 g of (7) as a white solid, m.p. 153°-155° C.

The procedure of Example 5(b) was followed, using 1.26 g (3.47 mmol) of tris(4-chlorophenyl)methanol, 0.52 g (5.1 mmol) of 1,2,4-triazole-3-thiol, 4.0 mL of CH2Cl2 and 1.25 mL (10 mmol) of BF3 etherate. Isolation followed by flash chromatography (75 g SiO2, 40% EtOAc-hexanes) gave 0.51 g of the title compound, followed by 0.71 g of an unstable product that turned into the title compound up on standing in solution. A 0.44 g sample of the first-eluted material was recrystallized from MeOH giving 0.18 g of (15), m.p. 219°-221° C. (dec).

IR (KBr) 1490, 1399, 1257, 1097, 1013, 815 cm−1.

NMR (CDCl3): δ6.75 (d, J=9, 6H); 7.05-7.3 (m, 18H); 7.59 (s, 1H).

Anal. Calc'd (C40H25Cl6N3S):

C, 60.62;

H, 3.18;

N, 5.30.

Found:

60.72;

3.41;

5.23.

EXAMPLE 71-(2-Chlorotrityl)-3,5-dimethylpyrazole (9)

a. To a stirred, ice-cooled solution of 2-chlorobenzophenone (21.6 g, 100 mmol) in 150 mL of dry Et2O under N2 was added 60 mL (120 mmol) of 2.0 M phenyllithium solution in cyclohexane-Et2O (7:3), keeping T<15° C. After stirring for a further 1 h at 15° C., the solution was poured onto crushed ice and extracted with Et2O. The organic solution was washed with 0.2 M H2SO4, water (until neutral), brine, dried (MgSO4), filtered and concentrated. The residue was recrystallized from hexanes containing a few per cent EtOAc to give 23.1 g (78%) of (2-chlorophenyl)diphenylmethanol as an off-white solid.

b. The above alcohol (4.20 g, 14.3 mmol) was dissolved in SOCl2 (5.0 mL, 68 mmol) under N2. The nitrogen line was replaced with a CaSO4 drying tube. After a 1-min induction period, gas was rapidly evolved (CAUTION!). A further 3.4 mL (47 mmol) of SOCl2 was added, followed by 4 mL of toluene. Stirring was continued for 6 h. The solution was then concentrated under reduced pressure, the residue dissolved in toluene, concentrated and vacuum pumped to give 4.40 g (99%) of (2-chlorophenyl)diphenylchloromethane as a solid.

c. Periodic acid (1.90 g, 8.33 mmol) was added to a stirred solution of the above epoxy ether (2.87 g, 6.4 mmol) in 60 mL of dry Et2O and 15 mL of CH2Cl2. After 1 h, the solution was washed with saturated NaHCO3, water (until neutral), brine, dried (MgSO4), filtered and concentrated giving 2.63 g of crude aldehyde as a foam. This material was dissolved at once in 60 mL of MeCN.

d. Morpholine (0.23 mL, 2.6 mmol) was added to a 12 mL portion of the above aldehyde/MeCN solution, followed by NaBH3CN (0.25 g, 4.0 mmol). After 30 min the reaction was quenched with HOAc (2 mL), allowed to stand for 15 min, and poured into saturated Na2CO3. The crude product was isolated by EtOAc extraction and purified by flash chromatography (70 g SiO2, 40% EtOAc-hexanes) giving 0.32 g of a solid. This material was recrystallized from EtOH, giving 0.21 g of (5), m.p. 151°-153° C.

N-(2-hydroxyethyl)piperazine (0.32 mL, 2.6 mmol) was added to a 12 mL portion of the aldehyde/MeCN solution of Example 11(c). The mixture was quenched and extracted as above, and the crude free base dissolved in EtOH and treated with maleic acid (0.085 g, 0.73 mmol). The resulting solution was concentrated and triturated with Et2O giving a white solid, which was recrystallized (EtOH-EtOAc) to give 0.05 g of (6), m.p. 173°-176° C. (dec).

A solution of (2,6-dichloro-3-methylphenyl)diphenylmethanol (0.40 g, 1.2 mmol) and imidazole (0.50 g, 7.4 mmol) in 2 mL of acetic acid was heated to reflux for 2 h and then allowed to stand at RT for two days. The product was isolated by EtOAc/H2O partition followed by chromatography (75 g SiO2, 50% EtOAc-hexane) to give 0.40 g (87%) of (16) as a white foam.

Tablet: 10-1000 mg of non-steroidal glucocorticoid antagonist with inactive ingredients such as cornstarch, lactose, colloidal silicon dioxide, microcrystalline cellulose, and magnesium stearate can be formulated according to procedures known to those skilled in the art of tablet formulation.